Ralph Burmester: What did you expect when you first came to Lindau in 1993?

Edmond Fischer: I remember well the first time I ever heard of Lindau. It must have been forty-fifty years ago; I was flying to Europe on TWA and, seated behind me, was George Wald. While we were chatting together, he told me he was going to a place called Lindau, on Lake Constance, where Nobel Laureates would be giving lectures to many students. And I thought: what an incredible experience it must be for young researchers to hear some of the foremost scientists discussing their work in such an informal setting. What a rewarding experience it must be for the laureates to have this opportunity to communicate with very bright students from all over the world. So, it’s no wonder that, when I was in Stockholm in 1992 for the Nobel Award Ceremony and I was invited by Count Lennart and Countess Sonja to attend the Lindau Meeting, I accepted with enthusiasm.

How did you perceive the Nobel Laureate Meetings personally?

I went to Lindau for the first time with my wife Bev in 1993, and the meeting was all that we had expected, and more. We were overwhelmed by the gracious and friendly way we were received. We were all lodged at the stylish and charming old Bad Schachen Hotel with its lovely lakeside garden, and we often walked together along the lake to the Inselhalle were the meetings were held. There were several friends of us and we met many other laureates whom we knew only by name. The opening ceremony was both solemn and whimsical, with the display of extravagant hats by Countess Sonja, and the talks and other events including the Friday trip to Mainau were outstanding.

The meetings have been planned for them, for the students, not for the laureates.

Which elements of these meetings do you hold so dear that they make you return every once in a while?

Meeting many friends, both from Lindau and fellow laureates. Having an opportunity of encountering recent laureates whom I didn’t know and listening to their superb presentations. And, of course, the prospect of meeting and speaking with students from all over the world. The meetings have been planned for them, for the students, not for the laureates.

In your opinion, which dimension of these meetings is more beneficial, the scientific or the social one?

Undoubtedly, their scientific contribution. Social occasions are obviously very pleasant, because they allow one to interact with people and provide some needed relaxation amid very intense activities, but they are secondary to the mission of the Lindau Meetings which is to inspire, motivate and connect.

What kind of topics are you discussing with young researchers?

Obviously, topics related to one’s field of expertise. The students come to you after having heard your talk and realise that some of the material you covered is relevant to their own research project. And those already involved in scientific research are eager to tell you what they are doing.

Since the interdisciplinary Jubilee Meeting the scientific standard is reported to have much improved – thanks to the committee of organisers here. It has also become much more international. I wonder how you perceived this development – was it much to your convenience?

Yes, indeed. The quality of students has improved enormously. I remember well, 20 years ago, meeting a bunch of students who were not even in science. They came to Lindau to have fun, to camp with friends. Some didn’t attend any lectures or group discussions. Lindau was barely known at that time. Universities and most of their faculty had never heard of it and there was no incentive for them to suggest students or write letters of recommendation on their behalf. Today, in contrast, the Lindau Meetings are known throughout the world and there is almost a competition among institutions to have their students admitted, and they feel highly honoured when this occurs.

How do you like the interdisciplinary meetings which have been set up every five years from then on?

Very much. It is an occasion to learn what is going on and what is new in different fields of science, and to meet the friends we have in those other disciplines. In fact, those are my preferred meetings.

What – in your eyes – are the factors that contribute to making the Lindau Nobel Laureate Meetings a true success?

Superb lectures, the beauty of Lindau and Bad Schachen, and Mainau, and the warmth, kindness and friendliness with which we are received.

What is the ‘Spirit of Lindau’ to you?

I now feel as if I were part of the Lindau family.

What are your hopes and expectations for the future of the Lindau Nobel Laureate Meetings?

They can only increase. It’s like an opera: it takes years before everything runs to perfection. In my opinion, under the guidance of Sonja and Bettina, the meetings are now running flawlessly and with enormous efficiency. They run like a very well-oiled machine.

Furthermore, the quality and dedication of the students is unprecedented.

The genetic code is a sequence of letters spelling instructions for a cell’s normal growth, repair and daily housekeeping. Now, evidence is growing for a second code contained in DNA’s tangled structure. The location and packing density of nucleic acids may control which genetic instructions are accessible and active at any given time. Disrupted genome structure could contribute to diseases such as cancer and physical deformities.

To fit inside a cell, DNA performs an incredible contortionist feat, squeezing two metres of material into a nucleus only a few micrometres wide. DNA compacts itself by first wrapping around histone proteins, forming a chain of nucleosomes that looks like beads on a string. Nucleosomes then coil into chromatin fibres that loop and tangle like a bowl of noodles.

To reveal the structural genetic code, researchers examine chromatin from its sequence of nucleotides to the organisation of an entire genome. As they develop microscopy techniques to better visualise the details of chromatin structure, even in living cells, they’re better able to explore how structural changes relate to gene expression and cell function. These developing pictures of chromatin structure are providing clues to some of the largest questions in genome biology.

Chromatin compartments

A prevailing theory about chromatin structure is that nucleosomes coil into 30 nm fibres, which aggregate to form structures of increasing width, eventually forming chromosomes. The evidence for this comes from observing 30 nm and 120 nm wide fibres formed by DNA and nucleosomes purified from cells.

A team led by Clodagh O’Shea, at the Salk Institute for Biological Studies wondered what chromatin looked like in intact cells. In 2017, the researchers developed a method to visualise chromatin in intact human cells that were resting or dividing. The researchers coated the cells’ DNA with a material that absorbs osmium ions, enabling the nucleic acid to better scatter an electron beam and by doing so appear in an electron micrograph. Next, they used an advanced electron microscopy technique that tilts samples in an electron beam and provides structural information in 3D. The researchers noticed that chromatin formed a semi-flexible chain 5 to 24 nm wide that was densely packed in some parts of the cell and loosely packed in others.

“We show that chromatin does not need to form discrete higher-order structures to fit in the nucleus,” said O’Shea. “It’s the packing density that could change and limit the accessibility of chromatin, providing a local and global structural basis through which different combinations of DNA sequences, nucleosome variations and modifications could be integrated in the nucleus to exquisitely fine-tune the functional activity and accessibility of our genomes.”

Along with packing density, location is another component of chromatin structural organisation. Researchers have known for three decades that chromatin forms loops, drawing genes closer to sequences that regulate their expression. Biologist Job Dekker, at University of Massachusetts Medical School in Worcester, and his colleagues have developed several molecular biology-based techniques to identify neighbouring sections of chromatin 200,000 to one million bases long. One of these techniques, called Hi-C, maps chromatin structure using its sequence.

In Hi-C, researchers first chemically crosslink the nucleic acid to join portions of chromatin that are near each other. Then they use enzymes to cut the crosslinked chromatin, label the dangling ends with a modified nucleotide, and reconnect only crosslinked fragments. Finally, the researchers isolate the chromatin fragments, sequence them, and match the sequences to their position in a cell’s whole genome.

In 2012, Bing Ren, at the University of California, San Diego School of Medicine,and colleagues used Hi-C to identify regions of chromatin they called topologically associating domains (TADs). Genes within the same TAD interact with each other more than with genes in other TADs, and domains undergoing active transcription occupy different locations in a nucleus than quiet domains. Altered sequences within a TAD can lead to cancer and malformed limbs in mice.

The basic unit of a TAD is thought to be loops of chromatin pulled through a protein anchor. Advanced computer models of chromatin folding recreate chromatin interactions observed using Hi-C when they incorporate loop formation. But genome scientists still aren’t sure which proteins help form the loops. Answering that question addresses a basic property of DNA folding and could point to a cellular mechanism for disease through mutations in a loop anchor protein.

Super resolution microscopy

Advanced optical microscopy techniques, based on a method recognised by the 2014 Nobel Prize in Chemistry, are also providing information about how regions of chromatin tens of bases long could influence cell function. Super-resolution fluorescence microscopy enhances the resolution of light microscopes beyond the 300-nm diffraction limit. This technique uses a pulse of light to excite fluorescent molecules, and then applies various tricks to suppress light shining from those molecules not centred in the path of the excitation beam. The result is the ability to image a single fluorescent molecule.

Biological molecules, however, can carry many fluorescent labels, making it difficult to localise a single molecule. Using fluorescent labels that switch on and off, researchers activate and deactivate fluorescent molecules in specific regions at specific times. Then they stitch the images together to capture the locations of all the fluorescent tags.

Xiaowei Zhuang, at Harvard University, and colleagues used super resolution microscopy to follow how chromatin packing changed based on its epigenetic modifications. Their method provided images on a scale of kilobases to megabases, a resolution between that of pure sequence information and large-scale interactions available through Hi-C. Information about gene regulation and transcription happens on this scale. This technique also offers the potential of imaging nanometre-scale structures in live cells.

Structural dictionary

Using a variety of methods to capture static and dynamic cellular changes, researchers around the world are working to write a dictionary of the structural genetic code throughout space and time. The 4D Nucleome Network, funded by the National Institutes of Health, and the 4D Genome project, funded by the European Research Council, are identifying a vocabulary of DNA structural elements and relating how that structure impacts gene expression. They’re also curious about how chromatin structure changes over the course of normal development as well as in diseases such as cancer and premature aging. With many basic questions outstanding, much remains to be discovered along the way.

During the late 1990s, investors were eager to invest in any company with an Internet-related name or a “.com” suffix. Today, the word “blockchain” has a similar effect. Like the Internet, blockchains are an open source technology that becomes increasingly valuable as more people use it due to what economists call “the network effect”. Blockchains allow digital information to be transferred from one individual to another without an intermediary. Bitcoin was the first use of the blockchain technology. However, the volatility, transaction fees, and uncertain legal framework have stalled Bitcoin’s widespread adoption.

The creator of Bitcoin, Satoshi Nakamoto, combined several ideas from game theory and information science to create Bitcoin. The basic idea for the blockchain technology originated with two cryptographers named Stuart Haber and Scott Stornetta. Their research focused on how to chronologically link a list of transactions. Today, when people refer to a blockchain, they are referring to a distributed database that keeps track of data. The type of data that the Bitcoin blockchain tracks is financial. Bitcoin users can send accounting units that store value from one user’s account to another user’s account without intermediaries. Since the Bitcoin Blockchain sends financial data and relies on cryptography, the accounting units in the blockchain are referred to as cryptocurrencies. The accounting units are stored in digital wallets, which are like bank accounts.

As a cryptocurrency, Bitcoin was designed to be a store of value and a payment system combined in one. Bitcoin has a fixed supply capped at 21 million and the currency’s inflation rate is programmed to decrease by half about every four years. Since Bitcoin was launched in 2009, the transactions on the network have doubled every year and the value of Bitcoin has increased by 100,000 percent. The current market price of approximately $11,500 is the result of the cryptocurrency’s limited supply and increasing demand.

The blockchain is a distributed database that stores a continuously growing list of all the transactions between the users. Imagine a Google Drive Document that has thousands of collaborators around the world that are constantly updating the information in the document. Like Google Docs, each editor sees the same information in the document, and when updates are made, each editor’s Google Doc shows the new changes. Like Google Docs, the Bitcoin blockchain stores the same duplicate database in thousands of locations throughout the world. This ensures that the database and the network cannot be easily destroyed.

When your hard drive crashes right before your doctoral dissertation is due, you are in big trouble. If you had used Google Docs or Overleaf instead, your data would be easily recoverable. To destroy an open source software, every single computer that has downloaded the software must be destroyed. This feature of the blockchain technology makes it the best method for preserving important information.

In addition to being hard to destroy, Bitcoin is a major technological breakthrough because Bitcoin solves the double-spend problem. Double-spending is the digital version of counterfeiting fiat currency or debasing a physical commodity money, such as gold. To solve the double-spend problem, Bitcoin relies on the “proof-of-work” consensus mechanism that I explained in my last article for the Lindau Nobel Laureate Meetings Blog. Proof-of-work is an incentive structure in the Bitcoin software that rewards Bitcoin users who make successful changes to the database. The users that are responsible for these changes are called “miners”. These individuals or groups of individuals listen to new incoming Bitcoin transactions using special hardware. Miners create blocks containing a list of the newest transactions that have been broadcast to the network by users. After approximately ten minutes, the transaction will be confirmed by all of the computers in the network. Next, blocks are added one after the other in a chronological order, creating a chain, hence, the name, blockchain. Each miner stores a copy of the entire Bitcoin blockchain and can see all changes that are being made as new transactions are settled on the network. Transparent accounting ensures that users cannot double-spend the same Bitcoin or create new bitcoin out of thin air.

Advancements in technology are a constant factor of the world around us. Artificial Intelligence (AI), Internet of Things (IOT), and Geolocation are just some of the buzzwords that we must add to our vocabulary. Bitcoin and Blockchain are two more terms to add to the list of potentially life-changing technologies. Whether the cryptocurrency market’s value will follow the same trajectory as the dot-com stocks is yet to be seen; however, the blockchain technology, like the Internet, is a revolutionary technology that is most likely here to stay.

Ageing seems to be an inevitable part of life, in fact, every organism appears to have a pre-set limited life span, sometimes this covers several decades and sometimes merely weeks. Over the course of this life span, one cornerstone of the ageing process is the so-called “Hayflick limit”, named after Leonard Hayflick, who in the 1960s discovered that cultured normal human cells have a limited capacity to divide. Once that limit is reached, cell division stops and a state of replicative senescence is entered – a clear cellular marker for ageing. On a molecular level, this limit is due to shortening telomeres. Telomeres are specific regions at the end of chromosomes, and with each cell division, and thus genomic replication, this region gets shortened until the replication can no longer be completed.

This process explains the basic molecular ageing process for most cell types, not, however, for neurons. Because brain cells do not divide at all; therefore, the Hayflick limit cannot be the reason for their demise. Thus, the brain and its function should remain stable until the end of our lives. And yet, a major hallmark of ageing is loss of brain matter volume and loss of cognitive abilities – even in the absence of clear-cut neurodegenerative diseases, such as Alzheimer’s disease. Moreover, not everyone seems to be affected by age-related cognitive decline – there are several examples of cognitively sharp and highly functioning individuals well into their 80s and 90s and beyond, while other, seemingly heathy, seniors show severe cognitive impairments at the same age. What causes this difference? What causes our brains to stop functioning, and can we prevent this?

Let’s start at the volume loss: under “healthy” ageing conditions, i.e., without the occurrence of neurodegenerative diseases, the brain volume loss is due to a loss of connections rather than due to a loss of cells. In other words: imagine flying in a helicopter over a thick, green, leafy forest – you can barely see the ground underneath the treetops; this is your young, healthy brain. Years later, you’re flying over the same forest again. The number of trees has remained roughly the same, but now many of them have lost a few branches and leaves and now you can see the ground below.

A loss of synapses and dendrites would account for the structural (and functional) changes that occur in the aging brain. But why are they lost? Recently, several molecular changes that have long been used as senescence markers in dividing cell lines have also been found in aging neurons. For instance, an increase in senescence-associated beta-galactosidase activity and an age-dependent increase in DNA damage have been observed in aged mouse brains. Under healthy cellular conditions beta-galactosidase is an enzyme that catalyses sugar metabolism and thus plays a pivotal role in the cellular energy supply. Although the mechanisms behind it are still unclear, the enzyme accumulates in aging cells and is a widely used molecular marker for senescent cells. However, when it comes to its accumulation in neurons, there is some debate whether these changes are truly age-dependent. The mechanisms behind the accruing DNA damage also remain unclear since it couldn’t occur during cell division.

Leaving the cause of such changes aside – what are their consequences? Could they be the reason for age-related cognitive impairments? At least for the changes in galactosidase activity there could be a connection: increased activity of this enzyme results in a lower pH-level within the cells. This in turn affects the functionality of lysosomes – small vesicles with a very acidic pH that function as a “clean-up-crew” for used or malfunctioning proteins in the cell, which were first discovered by Nobel Laureate Christian de Duve. If the pH of the entire cell drops, the function of the lysosomes could be disturbed, leaving unwanted proteins to aggregate within the cell. If the cell is “preoccupied” with internal protein aggregates, outward functions such as signal transmission and the likes suffer, eventually leading to phenotypic changes such as cognitive decline. In a similar manner, accumulating DNA damage could also lead to functional changes.

Another reason why many synaptic connections are lost with age could be that as we get older, we learn and experience fewer new things. Neuronal connections, however, must be used to stay intact, otherwise they degrade.

As with many age-related ailments, life experiences and exposure to toxins also seem to affect our cognitive abilities in old age. For instance, according to a recent study, even moderate long-term alcohol abuse can negatively affect cognition in later years. However, an ongoing study at the Albert Einstein College of Medicine in New York also highlights the importance of ‘good’ genes. The Longevity Genes Project follows more than 600 so-called super-agers aged over 90 and is aiming to identify certain genes that promote healthy ageing. According to the lead investigator, Nir Barzilai, the goal is to develop specific drugs based on these genes and thereby halt or at least slow down the aging process.

Aside from certain genes that seem to positively affect the way we age, there is something else that has been shown to even reverse the aging process and its unpopular companions such as hair loss, decreasing muscle tone and cognitive decline: the blood of the young. In a much-hyped paper from 2014 researchers from Stanford University show that infusing old mice that are physically and cognitively impaired, with the blood of younger mice at least partially reverses the effects of ageing. After treatment, the old mice solved cognitive tasks faster and more accurate, their muscle tone improved and even their coats looked better again. Ever since then, Tony Wyss-Coray, the senior researcher of the paper, and his colleagues have been trying to identify the specific component that drives this improvement. With his startup company Alkahest he even ran a first very small human trial in 2017, which – if nothing else – proved that the treatment with young blood was safe. For this trial the researchers infused plasma (blood without the red blood cells) from young donors for four weeks into patients with mild to moderate Alzheimer’s disease. Although there were no apparent adverse effects of the treatment, the patients also did not improve when undergoing cognitive testing. However, the mechanisms underlying Alzheimer’s dementia are distinct to those underlying cognitive decline in healthy ageing individuals. Hence, cognitively impaired but otherwise healthy elder individuals might in fact benefit more from such infusions.

While we now know a lot more about age-related structural, cellular and molecular mechanisms that could lead to cognitive decline, a specific and unifying culprit has not yet been identified. Nevertheless, Wyss-Coray, Barzilai and others are currently working on finding a cure for age-related cognitive and physical decline, thereby hoping to turn aging from an inevitability of life into a minor error that could be cured.

When I was growing up as an economist, first at Essex University and then at the London School of Economics, I was hearing about the Nobel Prize and all the gossip around it and I thought those winning it must be some kind of superhumans, that every word that came out of them is a word of wisdom. I guess in economics in my formative years, there were indeed some superhumans around: Samuelson, Hicks, Arrow, Friedman, to name a few who made the subject what it is. But it is still puzzling to me why, as human beings, we attach so much importance to the few who have the medal in their hand. And it’s not new: in Classical Greece, a city would destroy part of its city walls when one of its young men got the Olympic wreath because with men like him it did not need walls to protect it. What would I not have given in those days to be in the company of the Nobel Laureates (or the Olympic athletes, for that matter) for a few days? Lindau does just that for a few hundred lucky young people.

Lindau succeeds in breaking the shyness barrier between young people still struggling with degree studies and silver-coloured gentlemen.

Of course, today, being on the other side of the fence, I also count myself lucky to be in the company of so many bright young people and so many of my fellow laureates. In Lindau, I enjoy most the quiet discussions around the dinner table or talking with a cup of coffee in hand until the coffee gets cold and undrinkable (please, next time hire an Italian barista!). Lindau succeeds in breaking the shyness barrier between young people still struggling with degree studies and silver-coloured gentlemen who have forgotten what it is like to study for a degree (regrettably, there are no living women laureates in economics), to the extent that the organisers feel they should set aside certain times where the laureates can be on their own. Credit should go to the organisers, Countess Bettina Bernadotte and the staff of the executive secretariat.

I decided to lecture about my more recent interests rather than the work that won me the prize: the future of work in the age of automation and robots. It is a fascinating topic, which has attracted a lot of attention on both sides of the argument – the doom and gloom scenario that there will be no meaningful work left for humans and all the profits from the robots will go to a few wealthy individuals and the optimists who claim that society as a whole will be better off and the sooner the robots take over the work the better off we will all be. I belong to the second category but not unconditionally. A lot of jobs will no doubt be taken over by robots but many more will be created, ranging from software engineers who will develop and feed the robots with data and instructions to carers who will look after the children and ageing parents of men and women engaged in the new economy. But inequality and the question of who will get the rewards from the robots’ work is a big unresolved issue; governments need to work hard to come up with credible policies for how to reduce poverty and achieve more equality if the optimistic scenario is to materialise. These last topics were hotly debated both at the side gatherings and in the final panel session of the meeting, of which I was fortunate enough to be a member, on a beautiful day in the lush gardens of Mainau Island.

Pissarides and young economists during the Lindau Meeting in 2017. Photos/Credit: Julia Nimke/Lindau Nobel Laureate Meetings

Lindau has been going on for a long time but it is an evolving organisation. This year, we had several 5-minute presentations by graduate students, which are much better than poster sessions where you wander around a room with posters hanging on its walls and students standing by them in the hope that someone will pay attention. The 5-minute presentations put laureates and student participants into the picture, enabled the students to say what their research objectives were and generated lively discussions afterwards in the gardens and coffee rooms of the island. If I have a grievance, it is that despite the length of the meeting (arrived Tuesday and left Sunday) there was still no time to visit the other attractions of Lindau Island, including, from what I am told, a wonderful old library. A free afternoon would have been welcome! This year, there were also more journalists with requests on one’s time for interviews, which interfered with participation in other laureates’ presentations, which is a shame given how much you learn from them. Journalists can reach many more people than can be present in Lindau so their presence should be welcome, but where one strikes the balance between time taken up in interviews with them and attendance at the scheduled events is something not easy to resolve.

Overall, this was an excellent meeting; regretfully, we have to wait three whole years for the next one.

More reviews and highlights of the 6th Lindau Meeting on Economic Sciences can be found in the Annual Report 2017.

In his speech at the presentation of Peter Badge’s ‘Nobel Heroes’ on 22 September 2017 at the Nobel Peace Center in Oslo, Bishop emeritus Gunnar Stålsett stressed the importance of science in times of global tensions. The former Vice Chair of the Nobel Peace Prize Committee was appointed a member of the Honorary Senate of the Foundation Lindau Nobel Laureate Meetings in 2013.

“The Nobel Peace Center is like the eye of the storm. Irma, Maria, Kim Jong-un and Donald Trump: in diverse ways they all wreak havoc for millions of people, and threaten disaster for our entire human habitat. To stem these destructive tides of extreme weather and human folly, we need the wisdom of science and the calm of common sense. Against hatred and intolerance we need education and civil courage. This is what Nobel science and Nobel peace is about. This is what we celebrate today: a confluence of academic knowledge and moral conviction. This is wisdom. This makes peace great again.

Every day, we are reminded of great threats to the human family and to our entire habitat. We are on the brink of a nuclear war. Hundreds of millions of lives are threatened by starvation and climatic catastrophes causing mass migration. National, ethnic and cultural extremism affect every region of the world. Violent religious extremism is seen in every religion. Hatred defeats the love of neighbours.

Against hatred and intolerance we need education and civil courage. This is what Nobel science and Nobel peace is about.

The will of Alfred Nobel emphasised fraternity, not enmity, between nations, the reduction of standing armies, not an escalation in the development of weapons of mass destruction, peace congresses, not unilateralism. His are practical steps even in the 21st century. The concerted efforts of people of good will across social, ethnic, cultural and religious divides, from one generation to the next, are what will bring about a better tomorrow. In a vulnerable world, there are victims and there are heroes. Sometimes heroes sadly fail. Sometimes victims win the day.

In the eye of the storm, it is still but not silent. Peace is dissent, expressed in loud protest. I believe we are all grieved by the tragic onslaught on the Rohingya Muslim population of Myanmar, not forgetting the tragedies of Syria and Yemen – to name but a few of the places where death and destruction reign.

Alfred Nobel wanted to strengthen those who conferred the greatest benefit to mankind. That is his legacy. That is our privilege. Here, in this centre, in the spirit of Nobel, we humbly affirm a foundation of shared human values on which to build the future. Peace is personal. The great Swedish humanist, Dag Hammarskjøld, the General Secretary of the United Nations who died in the pursuit of peace, speaks in words of prayer of the inner challenge we all face: “If only I may grow: firmer, simpler, quieter, warmer.”

Thank you, Countess Bettina Bernadotte, for inviting me to offer a few remarks on this special occasion. I have been greatly inspired by your leadership of the Council for the Lindau Nobel Laureate Meetings. You have continued the wise direction of your predecessors, your father Lennart and your mother Sonja. With eminent supporters and co-workers, such as Professor Wolfgang Schürer and Nikolaus Turner, the Lindau Nobel Laureate Meetings and its institutions have become the most significant academic encounter worldwide between Nobel Laureates and the new generations of scientists.

Whether Lindau or Stockholm or Oslo, we are united at the crossroads of human endeavour for peace and justice.

The occasion here today, the launching of Peter Badge’s ‘Nobel Heroes’, connects Lindau, Stockholm and Oslo as different members in one Nobel family, all dedicated to promoting the will of Alfred Nobel, through a symphony of science, peace and education. Peter has used his personal and professional skills to promote the Nobel legacy. No one has met more laureates literally, face-to-face, than he has. Through his photographic genius, we are brought closer to personalities who have contributed to fulfil the vision of Alfred Nobel. Life itself makes it impossible to isolate academic, scientific dedication from the challenges of responsible citizenship. I share the wish of Nobel Laureate in Physics Steven Chu when he says “I hope you, the young Lindau scientists, will be moved to use your considerable talents to help enrich and save the world.” In a nutshell, this is what science is about. This is what peace is about. This is the highest aspiration of the human intellect and the shared yearning of humanity. Whether Lindau or Stockholm or Oslo, we are united at the crossroads of human endeavour for peace and justice.

Let one example suffice: in the history of the Nobel Peace Prize, the abolition of weapons of mass destruction has most frequently been highlighted by the Prize Committee. The Lindau Nobel Laureate Meetings in 1955 issued the Mainau Declaration against the use of nuclear weapons. In 2015, Nobel Laureates initiated the Mainau Declaration on Climate Change. Both were signed by many laureates from all sciences. And both issues are shaping the agenda of heads of states this week at the United Nations.

The presence here today of one of the Nobel Laureates of 2011, Tawakkol Karman, reminds us of the importance of women for peace and in the struggle for freedom of thought, freedom of expression, freedom of faith and freedom from fear caused by oppression and war. Again, by bringing all laureates together, Peter Badge’s work helps us to transcend the categories of sciences, literature and peace and to see ourselves as one mankind in one global community with one mission.

Through the images of Nobel Laureates of all prizes, Peter Badge conveys a message without words. Through his lens we sense the greatness of the human mind and the depth of the human heart. I see his work, in the words of St. Francis of Assisi, as an instrument for peace.

Congratulations on your message of hope, your testimony of perseverance and not least, your trust in the human genius for good. Your interpretation of the past offers healing for the future.”

In summer 2017, renowned German publisher Gerhard Steidl released the coffee table book ‘Nobel Heroes’ (ISBN 978-3-95829-192-8). It compiles 400 portraits of Nobel Laureates by German photographer Peter Badge. The project, commissioned by the Lindau Nobel Laureate Meetings, is supported by the German foundation Klaus Tschira Stiftung.

This speech and other highlights of 2017 can be found in the Annual Report.

Few events in the career of a scientist make such a lasting impression as the Lindau Nobel Laureate Meeting. In the beautiful setting of Lake Constance, Countess Bettina Bernadotte and the staff of the executive secretariat of the Lindau Meetings welcome hundreds of young talents from all over the world to discuss with several Nobel Laureates. Far beyond my daily joy of discovery in the molecular world, I experienced the excitement and stimulating atmosphere created by the discussions with so many bright young minds. The lectures of distinguished Nobel Laureates, covering various aspects of our discipline and far beyond, were equally stimulating, providing ample opportunities to open new windows to our common future. This memorable event, characterised by superb organisation and royal treatment, makes even the youngest participant feel proud to be a scientist. The numerous discussions with the students reminded me vividly of my own early days as a young scientist – the wonder and passion for chemistry but also the struggle with choices. Which are the most challenging topics or areas for the future, which directions to take, how to deal with the winding and unpaved roads to discovery, the balance in one’s personal life? How do you translate the advice of one of your heroes in the field and find the balance with your own knowledge and intuition? It was indeed a great joy to rediscover how the journey of a scientist starts as well as sharing my personal experiences with these daring and ambitious young men and women.

Few events in the career of a scientist make such a lasting impression as the Lindau Nobel Laureate Meeting.

The opportunity to advocate the values of science in general – our responsibilities for humanity and the important role of ‘quality of thought’ in academic training, through extensive discussions with participants from around the world – reflects to me one of the major assets of the Lindau Meetings. This extends to the many opportunities to engage with the press to emphasise the beauty and power of chemistry as the central science and the key role of all the young talents gathered in Lindau in making major contributions to invent our future. The considerable efforts of the Lindau organisation in reaching out to the community at large are to be applauded. The inspiring lectures and high-level social events, including an enchanting ’Mexican Evening’, provided the proper ‘wings’ to make us all feel as though we were flying during this magnificent week.

For me, the absolute highlight of the event was the discussion forum, which lasted nearly two hours, with a large group of students. The topics ranged from personal highlights to decisive moments in my career, the challenging questions by the audience on the future of our discipline and the experiences shared by students from different continents, made this particular meeting a steep mutual learning curve for all of us. It was a fine example of the essence of science, asking questions and entering academic debate. It gave me much pleasure to share with the students my views on “how to discover your talent” being a scientist: “Be confident in following your dreams, as it allows you to discover what will give you lots of energy and to experience your limits in this adventure in the unknown beyond your current horizon.”

The joy of discovery by the students, both scientifically and personally, experienced in all its facets during the Lindau week, will make a long-lasting contribution to the careers of these young chemists. The Lindau Nobel Laureate Meeting offers a magnificent ‘laboratory’ for young talents who are going to shape our future.

More reviews and highlights of the 67th Lindau Meeting can be found in the Annual Report 2017.

Go on a virtual tour through the Feringa lab at the University of Groningen in the Nobel Lab 360°.

I must admit to being incredibly intimidated about attending the 6th Lindau Meeting on Economic Sciences. About twenty of history’s greatest minds coupled with hundreds of the world’s most talented young scholars on one island – I felt like a stowaway on a celebrity cruise, and I wondered how on earth I’d participate in their conversations without being discovered for the imposter I was.

But in hindsight, my fears were ill-founded. From the very first interaction at the airport arrivals, everyone I met was enthusiastic, approachable and, above all, friendly. I discussed how to best measure teacher quality and swapped job-market war stories with Chicago-based Nathan in the taxi ride from the airport and was amazed by the developments in climate finance after meeting Veronika, a Russian physicist, in the hotel lobby. Rushing off to dinner, I sat opposite Banji, who educated me about the consequences of Nigeria’s trade policy on its energy markets, and Eleni, who detailed the early results of a cash transfer pilot study in Ethiopia. On the bus, Roxana from Romania taught me a form of econometrics I didn’t even know existed. By the time I fell asleep that night, my notebook already had pages full of scribbles about the people I’d met and the conversations I’d had – and the official programme hadn’t even begun.

But it was the interactions with the laureates themselves that really surprised me. I had expected these esteemed statesmen to be cordial and pleasant – which they were – but I had not expected them to go so far beyond their official obligations (for lack of a better word). The laureates were not only tirelessly willing to acquiesce to our floundering flattery and sycophantic selfies, but were eager to interact with us on an intellectual level, engaging in stimulating conversation with different groups of scholars at every possible break in the programme. They actively encouraged us to ask the big questions, whether it was about their work, our own careers or the state of the science itself. They listened to our views, not dismissively or with well-crafted rebuttals but with real consideration. And while it was hard to ignore their obvious intellectual aura, on several occasions the laureates showed us their human sides and let their hair down (who knew they could dance like that?). One common thread of advice I picked up from the laureates was their earnest desire that young economists take up relevant, welfare-improving research topics, rather than just playing the classic publishing game. Coming from a policy background and thus a ‘late-starter’ to the world of academia, I very much appreciated hearing this admonishment – though one could imagine it is easier to dish out, let alone follow, with a Nobel Prize hanging in one’s office… Having said that, I found that this idealism was echoed by my fellow scholars, and it was a delight to listen to their presentations and the laureates’ comments in the parallel sessions – not to mention the many animated conversations we had over dinners, coffees and even swims in the lake. Judging by these short snapshots of research, it was even possible to imagine a few of them standing in front of the Swedish monarch at some point in the future.

I didn’t anticipate such positivism in a room full of economists, but on reflection I guess that’s what the Lindau Meetings are all about.

I particularly enjoyed chatting with people from vastly different streams of research to mine – including, mind you, other attendees such as the laureates’ and scholars’ partners, members of the Lindau Council and its executive secretariat and industry partners. In the cut-throat world of academia, it’s so easy to lose one’s self in the narrow silos into which we now specialise, so it was an unexpected pleasure to have such stimulating debates that combined all branches of economics and policy, joined by a common focus on real-world issues (I’d forgotten that macroeconomics can actually be fun). More importantly, there appeared to exist a collective motivation among the scholars that our careers should matter in some tangible way to the ‘outside world’ and that the investment made by ourselves and others in our education deserved to be returned with real contributions to improving welfare. To be honest, I didn’t anticipate such positivism in a room full of economists, but on reflection I guess that’s what the Lindau Meetings are all about.

It was surprisingly sad to leave Lindau after such a brief but hectic event. Sure, I’d been running on caffeine and naps for a week, visited the first-aid tent twice and had run out of clean socks, but attending the Lindau Meeting was, pardon the cliché, an unforgettable experience. I landed home with a folder overflowing with lecture notes, research ideas scribbled on napkins and crumpled business cards of the scholars and other attendees, all thanks to the wonderful opportunity that the Foundation and the Council for the Lindau Nobel Laureate Meetings provided. It’s an opportunity I’m not going to waste.

David Smerdon gave the farewell address of #LiNoEcon alongside Nobel Laureate Jean Tirole.

More reviews and highlights of the 6th Lindau Meeting on Economic Sciences can be found in the Annual Report 2017.

The Nobel Prize Award Ceremony is traditionally held on 10 December, the day Alfred Nobel died in 1896, and the Nobel Week in Stockholm is arranged around this date. The three new Nobel Laureates in Chemistry are all expected to attend: Jacques Dubochet, Richard Henderson and Joachim Frank. They are honoured for their contributions to the development of cryo-electron microscopy, or cryo-EM. Besides their scientific achievements, it is also worth looking at their respective personalities – they are all real characters. And although all three are very different indeed, they have one thing in common: They were all asked countless times by their colleagues why they were pursuing a seemingly ‘hopeless topic’. As we can see this week, sometimes it pays off to work on subjects not many people are interested in.

The Francophone Swiss Jacques Dubochet describes himself on his website as the “first official dyslexic in the canton of Vaud – this permitted being bad at everything.” Apparently, his reading problems caused his school grades to slide so much that his parents sent him to a boarding school to pass his federal maturity exam. “I was a terrible student and now I’m a Nobel Laureate: any questions?” he says and smiles – Dubochet is always good for a joke.

Another funny incident: A few weeks after the Nobel Prize announcement in early October, Dubochet was at a conference at EMBL in Heidelberg, the very institute where he developed his famous method to produce vitrified water for cryo-electron microscopy. Now as he entered one of the labs, he saw a cryo-electron microscope standing there and commented: “Now, this is a wonderful machine, but, unfortunately, I forgot what it can do.” Everybody laughed, because he is one of the main pioneers in this field.

A long-time challenge for cryo-EM had been the fact that the natural environment for most molecules is water, but water evaporates in the microscope’s vacuum. Freezing is one solution, but then the water crystallises, distorting both the sample and the picture. Now Dubochet came up with an innovative approach: He would cool the samples so rapidly that the water molecules had no time to crystallise. This left the molecules in a ‘glass pane’, freezing them in time, direction and in their natural shape. These cells weren’t alive anymore, but in a close-to-living state.

Though he’s an excellent scientist, Jacques Dubochet is also a man of many talents. “He has a unique power to pull his audience in,” says Marek Cyrklaff, Dubochet’s former EMBL colleague and long-term friend. “And he has a special structure of thinking, like being a dual person in one body,” Cyrklaff continues. “On the one hand, he’s a hardcore physicist, on the other, a top philosopher. The latter helps him to see far ahead, have visions, the former allows him to approach these goals in a structured way.”

He is also spontaneous, unconventional and “against all dogmas, in science and politics alike.” During his twenty years at the University of Lausanne, he has “devoted a lot of effort to the curriculum ‘biology and society’, and Lausanne at that time was unique in developing this curriculum for all our students,” as Dubochet himself explains on the telephone with Adam Smith from the Nobel Foundation. “It was not the kind of additional piece of education, it was a core programme in the study of biology. (…) The idea of this course is to make sure that our students are as good citizens as they are good biologists.” He still teaches in this programme, and he says that it’s very close to his heart. He’s also a member of the local council of Morges, where he lives with his wife. The day he learned that he was now a Nobel Laureate, he went to a council meeting in the evening.

Richard Henderson is originally from Scotland and has worked at the MRC Laboratory of Molecular Biology now for over 50 years. Photo: MRC-LMB

Richard Henderson attended the same EMBL conference in November 2017 as Dubochet. In a pre-dinner speech, Werner Kühlbrandt, Max Planck Director in Frankfurt, described his time in Cambridge where he received his PhD at the MRC Laboratory of Molecular Biology – and where Henderson had his own research group and later became director. “Richard never missed any of these occasions to meet and ‘have a chat’, as he would put it,” Kühlbrandt says, and “the discussions would continue at the lunch table, usually with Richard scribbling diagrams and quick calculations on the paper napkin.” Marek Cyrklaff also remembers Henderson never sitting in his office, but usually standing in the hallway and discussing projects with his colleagues.

If people now start to wonder when the LMB researchers ever finished their ground-breaking work, “the answer is very simple,” Kühlbrandt explains: “They talked to each other most of the day, but then worked doubly hard for long hours into the night.” He describes Henderson as “kind and helpful,” if strict and straight, as well as “a great optimist” – and to develop high-resolution cryo-EM, he needed to be an optimist.

Electron microscopes were believed to be suitable mostly for dead matter, because the powerful electron beam destroys biological material, and the specimens inevitably dry out in the microscope’s vacuum. Henderson started to tackle these problems in the early 1970s: He used a weaker electron beam and glucose solution to prevent the samples from drying out. In 1975, he was able to publish a low-resolution model of bacteriorhodopsin, a membrane protein. But that wasn’t good enough for him. Fifteen years later, in 1990, he succeeded in generating a three-dimensional atomic model of bacteriorhodopsin.

Richard Henderson describes himself as a ‘Scottish country lad’. When asked about “the biggest misconception” about his field of study, he replies: “That it is a boring technique rather than a minor art form.”

Joachim Frank is a German-American biophysicist. He was born in Germany during World War II, received his education in Germany, and moved to the US in the 1970s. Photo: Columbia University

Talking about art forms: Joachim Frank is not only a world-class scientist, he is also a published author. He has written numerous poems, short stories and three (to date unpublished) novels. On his website ‘Franx Fiction’, there is a selection of his published works. Under ‘Nobel Prize‘, he writes how a stranger recognised him in the New York City subway and asked: “How come you still take the subway?“ According to this blogpost, the most important perk for Frank is the fact that he doesn’t need to write any more review articles: “Assignments like this make sense if you want to add an epsilon increment to the chance of winning the Nobel Prize. But, as I said, I’m already here.”

In an interview with the Austrian newspaper Der Standard, published three days before the Nobel Prize in Chemistry was announced, Frank explains his motivation to write fiction: “It’s all about balance. Without my writing, I would feel very isolated. The world is such a beautiful and complex place, and science only has limited access to its wonders. Science is dominated by strict rules which preclude emotions, and I would never allow my emotions to influence my research. So, to balance out my life, I write fiction and take photographs.”

In his research, Joachim Frank developed an innovative image processing method, between the mid-1970 to mid-1980s, in which an electron microscope’s fuzzy two-dimensional images of many molecules are analysed and merged to reveal a sharp three-dimensional structure. For this purpose, his team at Wadsworth Center in Albany, New York, devolped the image processing programme SPIDER. With this tool, the researchers were able to generate very detailed images of ribosomes, and Frank studied these, among other proteins, for three decades.

In 2014, Frank was awarded the Benjamin Franklin Medal in Life Science, and a video from the Frankling Institute explains how his science knowledge also adds to his artistic appreciation of the world. In the video, Frank explains how once, driving through the woods, “this idea occured to me, that in every cell of every leaf of every tree, there are ribosomes doing this thing,” and he shows with his hands the ratched-like motion of ribosomes that he discovered. “And it made me realise that I’m the only one who has this epiphany right now, because nobody drives around with this kind of appreciation.”

Frank, Henderson and Dubochet will meet in Stockholm on 8 December for their Nobel Lectures and two days later for the Nobel Prize Award Ceremony. They have known each other for years, and now they will share this memorable week in Stockholm.

The resolution of electron microscopes has radically improved in the last few years, from mostly showing shapeless ‘blobs’ to now being able to visualise proteins at near-atomic resolution. This is why the magazine Nature chose cryo-EM as the Method of the Year 2015. Illustration/Credit: Martin Högbom/The Royal Swedish Academy of Sciences

Already in the 18th century, the astronomer Jean Jaques d’Ortous de Mairan found that plants continue to follow a circadian rhythm even when placed into a dark room overnight, suggesting the existence of an inner clock that was independent of the perception of the environmental cues that differentiate day from night. Later, researchers found that not only plants but also other organisms including humans have a circadian rhythm. Nobel Laureates in Physiology or Medicine 2017 Jeffrey C. Hall, Michael Rosbash and Michael W. Young deciphered the cellular mechanisms that make the inner clock tick using the fruit fly as a model organism.

Although these findings were underappreciated at the time, we now know that our circadian rhythms exert a profound influence on many aspects of our physiology. Our inner clock regulates our sleep pattern, eating habits, hormone levels, blood pressure and body temperature at different times of the day, adapting to concurrent changes in the environment as the Earth rotates about its own axis. Circadian clock perturbations have been linked to higher risks of cancer and cardiovascular disease. Intriguingly, recent research has shown that the adaptation to a 24-hour cycle is not restricted to species that are exposed to the drastic light and temperature changes during the day, and extends to the microscopic organisms that live deep within us.

We live in close symbiosis with trillions of microorganisms: Our microbiota plays an important role in many bodily functions including digestion, immune responses and even cognitive functions – processes that follow a circadian rhythm. The majority of our microbiota is found in the gastrointestinal tract. It turns out that these bacteria living in the depths of our gut themselves follow a circadian rhythm, and, further, that disruption of this rhythm also has negative consequences for our health. What’s more, perturbations of our inner clock affect the function of these bacteria and vice versa: the gut microbiome influences our circadian rhythm.

In 2013, French scientists demonstrated that gut microorganisms produce substances that stimulate the proper circadian expression of corticosterone by cells in the gut. Loss of bacteria from the intestine resulted in mice with several profound defects including insulin resistance. In a particularly eye-catching study from 2014, meanwhile, researchers based at the Weizmann Institute of Science in Rehovot, Israel, including Lindau Alumnus 2015 Christoph Thaiss, observed a diurnal oscillation of microbiota composition and function in mice as well as in humans and found that this oscillation was affected and disturbed by changes in feeding time as well as sleep patterns, i.e, perturbations of the host circadian rhythm. As a highly relevant example, they found that jet lag, for example, in people travelling from the USA to Israel, disturbed the rhythm of the microbiota and led to microbial imbalance, referred to as dysbiosis.

The bacteria in our gut also follow a circadian rhythm. Picture/Credit: iLexx/iStock.com

It is not only the timing of meals that affects the circadian clocks of our resident bacteria, but also what we eat. Thus, while a high-fat, Western diet naturally has direct effects on our bodies, a proportion of these effects is also mediated by the impact that such a diet has on our microbiota, which in turn acts to alter the expression of circadian genes in our bodies and disturb our metabolism. Further, a recent study showed that bacteria in the gut, through affecting our circadian rhythms, also influence the uptake and storage of fats from the food that we eat.

The circadian clock plays a critical role in immune and inflammatory responses, and it is thought that perturbations in the circadian rhythm make the gastrointestinal tract more vulnerable to infection. It has been shown in mice that a perturbed circadian rhythm indeed affects immune responses, suggesting that the time of the day as well as circadian disruption, such as jet lag or shift work, may play a role in the susceptibility to infections. In fact, the immune response of mice to bacterial infection with Salmonella is determined by the time of day, and disruption of the host circadian rhythm may be one approach that bacteria employ to increase colonisation.

These observations highlight once more the intimate relationship that we enjoy with our gut microbiota and the importance of circadian rhythms for both us, our bacteria and the relationships that bind us together. It is likely that the seminal findings of Hall, Rosbash and Young will continue to form the basis for further important insights for human health and for our relationships with other organisms. What we now know already has important and intriguing implications for human health. Indeed, it appears likely that a better understanding of the bidirectional relationship between the circadian clock and the gut microbiota may help to prevent intestinal infections. Further, they may allow us to determine optimal times of the day for the taking of probiotics or for vaccination against gut pathogens. It is also reasonable to assume that antibiotics have a markedly negative impact on the circadian clock of the gastrointestinal tract. Taken together, therefore, these findings offer a compelling scientific basis for the importance of regular sleep patterns and meal times in keeping us healthy.

“The quality of students has improved enormously:” In 2015, Nobel Laureate Edmond Fischer spoke to science historian Ralph Burmester about his first experience of the Lindau Meetings and their development since the early 1990s. ow.ly/8BFy30iqohF@DeutschesMuseum#LiNo15